Nebulizer Device Containing Aqueous Budesonide Composition

Abstract

Disclosed is a spray device for nasal or buccal delivery of a buffered aqueous composition comprising solubilized budesonide, buffered to a pH of 4-5, having improved long-term storage stability and reduced impurity levels, wherein the budesonide is dissolved at a concentration of at least 100 μg / mL, the composition is metal ion-free, filled into a sealed, metal-free first container with a spray pump system, and packaged in a sealed, oxygen-impermeable, oxygen-free second container, and the composition contains at least 90%, preferably at least 95%, of the nominal starting concentration of solubilized budesonide and 1% or less of total impurities relative to the budesonide concentration after storage for 12 months at 25° C. The invention further relates to a composition for use as a pharmaceutical in the treatment of inflammatory diseases or conditions.

Description

[Technical Field]

[0001] The present invention relates to a nebulizer device containing an aqueous buffered composition of solubilized budesonide having improved storage stability. [Background technology]

[0002] WO2017009480 discloses a method for substantially increasing the solubility of poorly water-soluble hydrophobic drugs in aqueous solutions. The method involves dissolving the hydrophobic drug in a suitable organic solvent and mixing the organic solvent with an aqueous buffer solution containing a saponin component selected from the group consisting of escin, glycyrrhizin, and Quillaja saponaria extract, together with dexpanthenol and, optionally, additional additives. The solubilization process is based on the formation of saponin micelles in a buffered aqueous environment.

[0003] One such poorly water-soluble drug is budesonide (CAS No. 51333-22-3), a glucocorticoid known to have anti-inflammatory activity, particularly as an agonist of the glucocorticoid receptor. It is therefore frequently used to treat pulmonary and intestinal inflammatory conditions, such as asthma, COPD, Crohn's disease, or ulcerative colitis. The solubility of this drug in water is less than 30 μg / ml. Attempts to solubilize budesonide according to the method disclosed in WO2017009480, i.e., dissolving budesonide in a phosphate-buffered aqueous solvent containing β-estrin, glycyrrhizin, polypropylene glycol, and dexpanthenol as essential ingredients, resulted in aqueous preparations containing up to approximately 850 μg / ml. While this dramatic increase in solubilized drug was certainly impressive, the long-term stability of the preparation was not entirely satisfactory, resulting in undesirable degradation of some of the material components and / or the formation of reaction products.

[0004] Thus, there was a need to overcome this deficiency and provide a stable aqueous preparation containing reasonably high concentrations of dissolved, or more precisely, solubilized, budesonide, essentially free of undesirable impurities from degradation and / or reaction products of some of the material components. Summary of the Invention

[0005] Solubilized budesonide formulations prepared according to the teachings of WO2017009480A1 typically contain dexpanthenol in a concentration range of 0.5-5% (w / v). Dexpanthenol is used in these formulations to maximize the solubilizing capacity of budesonide and stabilize the solubilization against precipitation during storage at room temperature, i.e., 20-25°C. As noted above, following the teachings of WO2017009480A1, it is possible to solubilize up to about 850 μg / ml of budesonide and maintain it in a solubilized state for long-term storage.

[0006] However, evaluation of the long-term storage stability of hydrophic drugs in aqueous solvent systems will not only involve determining the intact maintenance of drug concentration throughout the storage period, but will also include a check of the chemical stability of the entire solubilization system over the anticipated storage period.

[0007] Chemical degradation or decomposition of one or more material components of an aqueous buffered pharmaceutical composition, e.g., the active ingredient (API), as well as reaction products and / or degradation compounds that may result from chemical interactions between two or more material components, can limit stability. Such degradation, decomposition, and / or reaction products are generally considered undesirable impurities, preventing marketing approval and potentially limiting the availability of useful therapies.

[0008] It is therefore essential to remove such impurities, to the greatest extent possible, from aqueous formulations intended for use as pharmaceutical compositions and / or to find ways to avoid the occurrence of such impurities in aqueous solutions containing solubilized drugs.

[0009] With respect to solubilized budesonide formulations prepared according to the teachings of WO2017009480A1 and including dexpanthenol as part of the solubilization system, it has been found that the long-term storage stability of the formulations was substantially impaired by the gradual emergence of an initially unknown and unexpected contaminant (hereinafter designated "Impurity R"), as well as a second contaminant (hereinafter referred to as "Impurity D").

[0010] "Impurity D" is known in the art as 21-dehydro-budesonide, an oxidation product that gradually appears during storage of aqueous budesonide formulations at ambient temperature. It is not produced by chemical interaction with dexpanthenol or other components of the formulation.

[0011] Contrary to impurity D, structural analysis of impurity R revealed that it is the reaction product of budesonide with 3-amino-1-propanol (3AP). 3AP is a known contaminant of commercially available dexpanthenol, and its presence is permitted at concentrations of up to 0.5% in samples according to the European Pharmacopoeia (EP) and up to 1.0% in samples according to the United States Pharmacopoeia (USP). Furthermore, during storage of aqueous formulations containing dexpanthenol, 3AP forms in a time- and temperature-dependent manner due to hydrolysis, according to the reaction scheme shown in formula I. This hydrolysis reaction is relatively slow at neutral pH but accelerates under acidic or basic conditions. [ka]

[0012] When dexpanthenol is present in an aqueous solvent system together with budesonide, the following chemical reaction occurs during long-term storage (Equation II), resulting in the formation of 21-(3-hydroxypropyl)aminobudesonide, i.e., impurity R: [ka]

[0013] It was investigated whether reducing the concentration of dexpanthenol in a buffered aqueous composition, or completely removing dexpanthenol from the aqueous composition, would cause a substantial loss of drug concentration during storage in order to limit or prevent the formation of impurity R. From WO2017009480A1, it was known that dexpanthenol has both a solubilizing and a stabilizing effect on budesonide in buffered aqueous solvent systems.

[0014] However, quite surprisingly and unexpectedly, the reduction and complete removal of dexpanthenol from the experimental aqueous compositions did not cause precipitation of budesonide over several months of storage at room temperature. This surprising behavior may be due to experimental variations in the present aqueous solubilization system relative to that disclosed in WO2017009480A1, including the preferred selection of α-escin as opposed to β-escin as the saponin component, experimental budesonide concentrations lower than the 850 μg / ml used in WO2017009480A1, preferably 100-400 μg / ml, or typically 200 μg / ml, and adjusting the aqueous formulation to a lower pH than the 5.65 pH used in WO2017009480A1, preferably a pH of 4-5, typically about 4.3.

[0015] Escin: The current nomenclature for escin is based on distinguishing individual molecules contained in the component mixture, whereas previously used nomenclature distinguished the mixture of escin components based on their water solubility. The main fraction of naturally occurring escin mixtures obtainable from horse chestnut extracts consists of compounds with a protoesigenin skeleton esterified with acetic acid at C-22 and angelic acid / tiglic acid at C-21 (Geisler et al., 2019). This main fraction is called β-escin. In addition to β-escin, two other fractions have been identified in the escin mixture: α- and crypto-escin. α-escin is a mixture of crypto- and β-escin.

[0016] β- and crypto-estin differ in the position of the acetyl group in the backbone. In β-estin (also called estin 1a and 1b in more recent literature), this group is located at C-22, while in crypto-estin, it can be found at C-28. The latter are also called iso-estin 1a and 1b in more recent literature, where "a" denotes tigloyl and "b" denotes angloyl esterification (Savarino et al., 2023). Both forms can be distinguished by their aqueous solubility, their melting point, and their hemolytic index. For example, crypto-estin is water-soluble, whereas β-estin does not readily dissolve in water or buffers with a pH below 5 (Geisler et al., 2019). On the other hand, α-estin, a 4:6 mixture of β-estin and crypto-estin, is more water-soluble than pure β-estin. In addition, α-escin remains stable in water or aqueous buffer without dexpanthenol, whereas β-escin precipitates after several hours in water or aqueous buffer without dexpanthenol, but not in the presence of dexpanthenol. Therefore, we decided to select α-escin as the preferred saponin component for solubilizing budesonide in aqueous experimental samples. Commercially available escin preparations typically contain both α- and β-escin, but α-escin can be formed simply by heating an aqueous solution of β-escin, which causes acyl migration involving the hydroxyl groups at positions C21, C22, and C28.

[0017] Further improvements in storage stability have been achieved by reducing the occurrence of Impurity D. As disclosed above, the storage stability of aqueous preparations of solubilized budesonide is limited by the oxidation of budesonide, which results in the formation of 21-dehydrobudesonide (designated herein as "Impurity D"). The rate and rapidity of the formation of this Impurity D can be significantly reduced by preventing the permeation of molecular oxygen into the liquid preparation. This can be achieved, for example, by using protective secondary packaging that is impermeable to oxygen.

[0018] During the final steps of preparation of the liquid budesonide formulation, and during the subsequent steps of filling the liquid formulation into a primary container and packaging it in a secondary container under atmospheric pressure, small amounts of oxygen may still dissolve in the formulation and / or become part of the headspace of the primary and secondary containers. It has been experimentally determined that even these small amounts are sufficient to generate significant amounts of impurity D on storage.

[0019] One way to avoid such unwanted oxygen incorporation into the final formulation is to carry out the filling process under an inert gas atmosphere. Alternatively, or in addition, oxidation of budesonide can be limited by including oxygen absorbers inside the secondary packaging container, which are commercially available for the protection of oxygen-sensitive products.

[0020] For pharmaceutical development purposes, the effect of several external parameters on the formation of 21-dehydrobudesonide (impurity D) has been tested. It was hypothesized that by reducing O ingress from the ambient environment during storage, the formation of impurity D could be reduced even in the presence of iron and other metal ions in the liquid ready-to-use formulation.

[0021] Iron ions can leak into ready-to-use formulations from stainless steel tanks or piping during manufacturing. Furthermore, primary packaging, such as amber glass vials or nasal spray pumps, contains iron ions. These iron ions can catalyze the oxidation of budesonide via oxygen radicals. An initial series of experiments demonstrated that using HDPE vials instead of amber glass vials as primary packaging containers and implementing a completely metal-free manufacturing and filling process substantially reduced the formation of impurity D.

[0022] In a follow-up study, the content and purity of budesonide in ready-to-use formulations were monitored over time. The formulations were stored in primary packaging (HDPE vials) protected by secondary packaging, i.e., hermetically sealed, oxygen-impermeable bags additionally fitted with one or more oxygen absorber packets or sachets. To this end, buffered aqueous formulations containing 200 μg / ml budesonide and adjusted to pH 4.3 were prepared using different equipment for the manufacturing process: glass equipment only on the one hand, and stainless steel equipment on the other. Samples were stored in HDPE vials (Rochling, Germany) and sealed with either an APF or Classic Line nasal spray pump (manufacturer Aptar, Germany). Filled vials were stored in aluminum-coated bags, either unsealed or sealed, with or without O2 / H2O absorber sachets, at 25 and 40°C in a constant-climate chamber with controlled humidity. Samples were analyzed on day 0 and after 2 weeks, 1 month, and 3 months of storage. Budesonide content and related impurities were quantified using a validated RP-HPLC method. Additionally, the pH and appearance of the samples were recorded at each time point.

[0023] As a result of the above, when an oxygen absorber was used inside the secondary packaging container, excellent storage stability was achieved with substantially reduced formation of impurity D. If such an oxygen absorber releases water upon absorption of oxygen, it has been found to be advantageous to also include a desiccant inside the secondary packaging to eliminate the resulting moisture. [Brief explanation of the drawings]

[0024] [Figure 1] Representation of relative budesonide concentrations in aqueous buffer formulations containing solubilized budesonide, α-escin, and 0%, 2%, or 5% v / v dexpanthenol, expressed as a percentage of the nominal starting concentration of budesonide (i.e., 100%) recovered in samples after 12 months of storage at 25°C; analytical determination by HPLC; y-axis: concentration of recovered budesonide expressed as % of the nominal starting concentration; x-axis: 0%, 2%, or 5% v / v dexpanthenol. [Figure 2]Representation of the content of impurity R in aqueous buffer formulations containing solubilized budesonide, α-escin, and 0, 2, or 5% dexpanthenol, determined by HPLC, after 12 months of storage at 25°C; y-axis: relative concentration of impurity R expressed as % of the corresponding recovered budesonide concentration; x-axis: 0, 2, 5% v / v dexpanthenol. [Figure 3] Representation of the content of impurity D in aqueous buffer formulations containing solubilized budesonide, α-escin, and 0, 2, or 5% v / v dexpanthenol, determined by HPLC after 12 months of storage at 25°C; y-axis: relative concentration of impurity D expressed as % of the corresponding recovered budesonide concentration; x-axis: 0, 2, 5% v / v dexpanthenol. [Figure 4] Representation of the content of total impurities (including impurities "D" and "R") greater than 0.1% as determined by HPLC after 12 months of storage at 25°C in aqueous buffer formulations containing solubilized budesonide, α-escin, and 0, 2, or 5% dexpanthenol; y-axis: relative concentration of accumulated impurities including impurities R, D, and possible further impurities, expressed as % of the corresponding recovered budesonide concentration; x-axis: 0, 2, 5 v / v dexpanthenol. [Figure 5]Impurity D content (expressed as a percentage of the budesonide content) of samples prepared in glass containers and stored for up to 6 months at 25°C in the indicated primary and secondary packaging. Data presented as average (n=2); 1 = APF-Glass-Sealed Plus, i.e., glass container fitted with an APF spray pump and packaged in a sealed bag containing O2 / H2O absorber material; 2 = Classic-Glass-Sealed Plus, i.e., glass container fitted with a classic spray pump and packaged in a sealed bag containing O2 / H2O absorber; 3 = APF-Glass-No-Seal, i.e., glass container fitted with an APF spray pump and no secondary packaging; 4 = APF-Glass-Sealed, i.e., same as 1 but without the O2 / H2O absorber; 5 = Classic-Glass-No-Seal, i.e., glass container fitted with a classic spray pump and no secondary packaging; 6 = Classic-Glass-Sealed, i.e., same as 2 but without the O2 / H2O absorber. [Figure 6] Impurity D content (expressed as a percentage of the budesonide content) of samples prepared in metal containers and stored for up to 6 months at 25°C in the indicated primary and secondary packaging. Data presented as average (n=2); 1 = APF-Metal-Seal Plus, i.e., metal container fitted with an APF spray pump and packaged in a sealed bag containing O2 / H2O absorber material; 2 = Classic-Metal-Seal Plus, i.e., metal container fitted with a classic spray pump and packaged in a sealed bag containing O2 / H2O absorber; 3 = APF-Metal-No-Seal, i.e., metal container fitted with an APF spray pump and no secondary packaging; 4 = APF-Metal-Seal, i.e., same as 1 but without the O2 / H2O absorber; 5 = Classic-Metal-No-Seal, i.e., metal container fitted with a classic spray pump and no secondary packaging; 6 = Classic-Metal-Seal, i.e., same as 2 but without the O2 / H2O absorber. [Figure 7]Impurity D content (expressed as a percentage of budesonide content) of samples prepared in glass containers and stored for up to 6 months at 40°C in the primary and secondary packaging indicated. Data presented as mean (n=2); 1=APF-glass-sealed plus; 2=Classic-glass-sealed plus; 3=APF-glass-not-sealed; 4=APF-glass-sealed; 5=Classic-glass-not-sealed; 6=Classic-glass-sealed. [Figure 8] Impurity D content (expressed as a percentage of budesonide content) of samples prepared in metal containers and stored for up to 6 months at 40°C in the primary and secondary packaging indicated. Data presented as mean (n=2); 1=APF-Metal-Sealed Plus; 2=Classic-Metal-Sealed Plus; 3=APF-Metal-Not Sealed; 4=APF-Metal-Sealed; 5=Classic-Metal-Not Sealed; 6=Classic-Metal-Sealed. [Figure 9A] , [Figure 9B] Budesonide drug content during storage of dexpanthenol-free samples prepared in glass containers and stored for up to 6 months at 25, 30, and 40°C in the indicated primary and secondary packaging. Data presented as mean (n=2); a=APF, 25°C; b=Classic, 25°C; c=APF, 30°C; d=Classic, 30°C; e=APF, 40°C; f=Classic, 40°C; Figure 9A: Budesonide content expressed in absolute values ​​(μg / ml); Figure 9B: Budesonide content expressed as % of initial value on day 0. [Figure 10A] , [Figure 10B] Impurity content during storage of dexpanthenol-free samples prepared in glass containers and stored in the indicated primary and secondary packaging at 25, 30, and 40°C for up to 6 months. Data presented as averages (n=2); a=APF, 25°C; b=Classic, 25°C; c=APF, 30°C; d=Classic, 30°C; e=APF, 40°C; f=Classic, 40°C; Figure 10A: Impurity D content expressed as % of budesonide content; Figure 10B: Total impurity content expressed as % of budesonide content.

[0025] Example 1: In situ formation of decomposition and / or reaction products during long-term storage of aqueous solubilized budesonide compositions [Table 1]

[0026] As can be seen from Figure 1, formulations containing 200 μg / mL budesonide dissolved in a buffered aqueous solution containing the ingredients listed in Table 1 and adjusted to a pH of 4.3 have a concentration-dependent adverse effect on the storage stability of experimental samples. More specifically, while formulations without dexpanthenol maintained budesonide stable in solution over a 12-month observation period at 20-25°C, the addition of 2% v / v dexpanthenol caused a decrease in recoverable budesonide from approximately 96% (no dexpanthenol) to approximately 94% (2% dexpanthenol), and the addition of 5% dexpanthenol caused a further decrease in recoverable solubilized drug to approximately 93% of the nominal starting budesonide concentration.

[0027] At the same time, the concentration of "impurity R" increases with increasing dexpanthenol concentration, as shown in Figure 2. Or, in other words, excluding dexpanthenol from the experimental samples prevented the in situ formation of impurity R during storage at ambient temperature. Furthermore, reducing or eliminating dexpanthenol in these formulations not only reduced or eliminated the formation of impurity R in the experimental samples, but also reduced the formation of impurity D (see Figure 3). It was quite surprising that a concentration-dependent reduction in the formation of impurity D was observed in the experimental samples.

[0028] Without being bound by theory, this unexpected finding could possibly be due to the formation of impurity R in the presence of dexpanthenol. This impurity R, i.e., 3-amino-1-propanol (3AP), is a basic compound with a primary amine functional group. With increasing concentrations of 3AP in the experimental samples, the pH also increased slightly, regardless of the buffer system used in the solvent. Considering that the formation of budesonide oxidation products (i.e., impurity D) is promoted at higher pH, this may explain the observed effect of a parallel increase or decrease in impurities R and D.

[0029] From this example, it can be further concluded that providing an aqueous solvent system for solubilizing budesonide under the conditions specified in Table 1 allows for the complete abandonment of dexpanthenol as an essential ingredient for maintaining budesonide in a solubilized state and stable for at least 12 months of storage at room temperature. As a beneficial side effect of eliminating dexpanthenol from aqueous budesonide formulations, the in situ formation of undesirable impurities R and D during storage of the liquid formulation is substantially reduced, as can be seen in Figure 4, which is a graphical representation of the sum of all impurities, including impurities R and D, determined by HPLC in the samples.

[0030] Example 2: Effect of sealed storage on the stability of liquid budesonide preparations Impurity D is formed by oxidation of budesonide at the C21 hydroxyl group to give an aldehyde group in return. This reaction is carried out with molecular oxygen and catalyzed by ions of transition metals such as, for example, iron, manganese, copper, zinc, nickel, etc.

[0031] Abbreviations used below: ACN Acetonitrile AD Distilled water EDTA Ethylenediaminetetraacetic acid HDPE High Density Polyethylene HPLC High-Performance Liquid Chromatography L / N Lot Number PG Propylene Glycol RP-HPLC Reversed-phase high-performance liquid chromatography RRF Relative Retention Factor SS Stainless Steel S / N Serial Number UV / Vis Ultraviolet / visible light The experimental budesonide preparation used in this study contained the following ingredients: Budesonide, micronized 0.207 mg / ml Propylene glycol 10% (v / v) Dexpanthenol 50mg / ml EDTA 1.00mg / ml Escin 0.3mg / ml Citric acid monohydrate 10.4mg / ml Trisodium citrate dihydrate 14.85mg / ml pH 4.3 Further associated equipment included: 10ml snap-on bottle, white, sterile / Rochling Medical Neuhaus GmbH Snap-on nasal spray pump, APF, 50μl / Aptar Crimp-on Nasal Spray Pump, Classic Line, 50μl / Aptar Sartopore 2 / Sartorius Bottle Top Filter / TPP Aluminum Coat Bag (Material: A20T(12μPET / 12μALU / 75μLDPE) / Long life for art O2 absorber ATCO FT100 (0.5 liters) / Long life for art H2O absorber (mini bag 1g) / Long life for art HPLC col. Agilent Eclipse Plus C18 150×4.6mm, 3.5μm / Agilent

[0032] Two experimental preparations with the same composition of ingredients (see above for details) were prepared in different containers: either glass or stainless steel. After sterilization, each preparation was filled into two different primary packaging systems: HDPE vials (Rochling, Germany) sealed with a 50 μl APF nasal spray pump (Aptar, Germany), or HDPE vials (Rochling, Germany) sealed with a 50 μl Classic line nasal spray pump (Aptar, Germany). The different primary packaging systems were stored unsealed or sealed in aluminum-coated bags, additionally containing O2 and HO absorber sachets. The preparations were stored at two different temperatures: 25°C at 65% relative humidity and 40°C at 75% rh. Samples were taken at day 0, 2 weeks, 1, 3 and 6 months of storage and analyzed for the most relevant stability-indicating parameters: budesonide content, impurity D content, impurity R content measured at 240 nm, the sum of all impurities present, and pH. Additionally, control identical preparations without the drug budesonide were prepared and filled in the same different primary packaging system and stored either unsealed or sealed under the same conditions.

[0033] Samples of each experimental preparation before final disinfection were also taken and subjected to HPLC analysis to check for possible filtration losses.

[0034] After filling, vials labeled "No Seal" were placed directly into a storage crate. Vials labeled "Sealed" were placed into an aluminum-coated bag and sealed using an appropriate sealing press, and vials labeled "Sealed Plus" were placed into an aluminum-coated bag additionally fitted with O2 and HO absorber sachets and sealed using an appropriate sealing press. For HPLC analysis of Day 0 content, samples of the experimental preparations were filled directly into HPLC sample vials rather than into the experimental container.

[0035] The experimental preparations were stored for 6 months in climate chambers set at 25°C / 60% rH or 40°C / 75% rH. A temperature logger was used to monitor and record the temperature during sample storage.

[0036] result: a) Preparations prepared in glass containers and stored in HDPE vials at 25°C The budesonide content decreased by 3-4.5% over 6 months. The best results, i.e., lowest drug loss, were achieved when an APF nasal spray pump was used to cap and seal the vial, and the sealed vial (=primary packaging) was placed in an oxygen-impermeable bag (=secondary packaging) that was hermetically sealed and additionally fitted with an O2 / H2O absorber sachet; the sample still contained 189.4 μg / ml budesonide after 6 months of storage, equivalent to 97% recovery based on the value at day 0.

[0037] Similarly, using a Classic Line nasal spray pump to seal the experimental vials and sealing the sealed vials in a secondary packaging bag containing an O2 / H2O absorber led to significantly lower content loss; the sample contained 188.3 μg / ml after 6 months of storage, equivalent to 97% recovery based on the value at Day 0. In general, use of the Classic Line nasal spray pump resulted in slightly greater drug content loss compared to the individual APF nasal spray pump samples.

[0038] On the other hand, the formation of impurity D in samples packaged using the APF nasal spray pump resulted in impurity D values ​​of 0.3-0.5% relative to the budesonide content. The lowest increase in impurity D was found in the sealed samples plus O2 / H2O absorber (see Figure 5).

[0039] In comparison, packaging with the Classic Line nasal spray pump led to an impurity D content of approximately 1.3% of the drug content after 6 months of storage at 25°C, except for samples stored in sealed plus O2 / H2O absorber secondary packaging, where the level of impurity D did not exceed 0.38% of the drug content. Values ​​are comparable to those obtained with the APF nasal spray pump primary packaging.

[0040] The impurity R content in samples stored at 25°C increases to 2% of the starting budesonide content, regardless of the choice of primary and secondary packaging.

[0041] Analytical determination of the sum of all impurities formed over a 6-month storage period at 25°C revealed that samples stored in sealed packaging plus O2 / H2O absorbers exhibited the lowest impurity content, i.e., 2.5-2.6% of the drug content, regardless of the choice of nasal spray pump. The highest overall impurity content was determined in samples packaged using the Classic Line pump (3.4% - unsealed, 3.5% - sealed). However, when using the APF nasal spray pump, secondary packaging had virtually no effect on the overall impurity sum, with total impurities reaching 2.5-2.7% of the starting drug content.

[0042] b) Preparations prepared in stainless steel containers and stored in HDPE vials at 25°C When experimental preparations were obtained from stainless steel metal containers, budesonide drug content decreased by 2-4% over 6 months when stored at 25°C / 60% relative humidity. The lowest content loss was found in samples packaged in HDPE vials using an APF nasal spray pump for closure and a sealing bag plus O2 / H2O absorber as the secondary packaging system; the sample still contained 189.6 μg / ml after 6 months of storage, which equates to 98% drug recovery based on the day 0 value.

[0043] When using vials capped with the Classic Line nasal spray pump and sealed in a bag plus O2 / H2O absorber, the experimental sample contained 188.4 μg / ml after 6 months of storage, corresponding to a 98% recovery based on the starting value on day 0. Again, using the Classic Line nasal spray pump closure system resulted in a slightly greater loss of drug content compared to the individual samples using the APF nasal spray pump closure system.

[0044] The formation of impurity D in samples packaged using the APF nasal spray pump resulted in an impurity D content of 0.2-0.8% of the budesonide content. The smallest increase in impurity D was found in samples labeled "Sealed plus O2 / H2O absorber."

[0045] In comparison, primary packaging using the Classic Line nasal spray pump for closure led to an impurity D content of approximately 2% of the drug content after 6 months of storage at 25°C; except for samples in the sealed bag plus O2 / H2O absorber secondary packaging system, which resulted in an impurity D content of only up to 0.6% of the drug content (Figure 6).

[0046] The impurity R content in samples stored at 25°C increases to 2% of the starting budesonide content, regardless of the choice of primary and secondary packaging.

[0047] Analytical determination of the sum of all impurities formed over 6 months of storage at 25°C revealed that samples stored in sealed packaging plus O2 / H2O absorber showed the lowest impurity content, i.e., total impurities in amounts of 2.4 and 2.8% of the drug content, regardless of the choice of nasal spray pump. The highest overall impurity content was determined in samples packaged using the Classic Line pump (4.3% - unsealed, 4.3% - sealed).

[0048] c) Preparations prepared in glass containers and stored in HDPE vials at 40°C Budesonide content decreased by 10-20% over 6 months in samples stored at 40°C / 75% relative humidity. The best results, i.e., lowest drug content loss, were achieved for samples packaged using an APF nasal spray pump to seal the HDPE vial and a sealing bag plus O2 / H2O absorber material as the secondary packaging system; the sample still contained 174.4 μg / ml after 6 months of storage, corresponding to 90% drug recovery based on the day 0 value.

[0049] Surprisingly, the greatest drug loss was detected when the Classic Line nasal spray pump was used with a hermetically sealed vial in a bag plus O2 / H2O absorber; the sample contained only 155 μg / ml budesonide after 6 months of storage, corresponding to an 80% recovery relative to the starting value on day 0. In general, the Classic Line nasal spray pump system caused greater drug content loss than the APF nasal spray pump system.

[0050] The formation of impurity D was lowest in samples stored in sealed secondary packaging plus an O2 / H2O absorber, resulting in an impurity D content of 0.42% of the budesonide content. Samples stored unsealed or sealed without an absorber contained impurity D in amounts of approximately 2.6 and 2.5% of the budesonide content, respectively.

[0051] In comparison, packaging using the Classic Line nasal spray pump resulted in an impurity D content of 8-12.6% of the budesonide content after 6 months of storage at 40° C. The impurity D levels were much higher than those determined when using the APF nasal spray pump in the primary packaging system (see Figure 7).

[0052] Not surprisingly, the impurity R content differed only slightly between the different types of primary and secondary packaging: samples packaged with the APF nasal spray pump contained 9.3-9.8% impurity R, while samples packaged with the Classic Line nasal spray pump contained 8.7-9% impurity R relative to the budesonide content.

[0053] Analytical determination of the sum of all impurities formed over 6 months of storage at 40°C revealed that samples packaged using the APF nasal spray pump exhibited the lowest impurity content, regardless of the choice of secondary packaging, i.e., total impurities amounted to 10.3-12.6% of the budesonide content. The highest overall impurity contents were determined in samples packaged using the Classic Line pump, i.e., 21.2% - no seal, 21.9% - seal plus O2 / H2O absorber.

[0054] d) Preparations prepared in stainless steel containers and stored in HDPE vials at 40°C Budesonide content decreased by 10-20% over 6 months in samples stored at 40°C / 75% relative humidity. The lowest loss was found in samples packaged using the APF nasal spray pump and sealing bag plus O2 / H2O absorber; the sample still contained 174.2 μg / ml after 6 months of storage, corresponding to 90% drug recovery relative to the day 0 drug content.

[0055] When experimental vials sealed with the Classic Line nasal spray pump and sealed in a bag plus O2 / H2O absorber were tested, the samples contained only 171.2 μg / ml after 6 months of storage (89% recovery based on the Day 0 value). Again, use of the Classic Line nasal spray pump with the experimental vials resulted in slightly greater drug loss compared to the situation with the experimental vials using the APF nasal spray pump sealing system.

[0056] Impurity D formation was lowest in samples packaged using an APF nasal spray pump and sealed in a bag plus O2 / H2O absorber. After 6 months at 40°C / 75% relative humidity, the samples showed an impurity D content of only 0.9% of the drug content.

[0057] In comparison, primary packaging using the Classic Line nasal spray pump led to impurity D contents of approximately 1.7-13.7% of the budesonide drug content, depending largely on the nature of the secondary packaging. The smallest increase in impurity D was found in samples stored in the sealed bag plus O2 / H2O absorber secondary packaging, i.e., 1.7% of the drug content (Figure 8).

[0058] Again, the impurity R content in samples stored at 40°C differed only slightly between the different types of primary and secondary packaging equipment. Samples packaged using the APF nasal spray pump contained 9.3-9.7% impurity R, while samples packaged using the Classic line nasal spray pump contained 8.7-9.5% impurity R relative to the budesonide content. Analytical determination of all impurities formed over a 6-month storage period at 40°C revealed that samples packaged using the APF nasal spray pump and sealed in a bag plus O2 / H2O absorber exhibited the lowest total impurity content, i.e., 10.7% of the budesonide content. Samples packaged using the Classic line nasal spray pump and sealed in a bag plus O2 / H2O absorber exhibited the second lowest total impurity content, i.e., 11.4% of the drug content. The highest overall impurity content was determined in samples packaged using the Classic line pump: 22.8% without sealing and 18.0% sealed.

[0059] Example 3: Effect of sealed storage on the stability of dexpanthenol-free liquid budesonide formulations Example 2 was repeated, except that the aqueous buffer composition did not contain dexpanthenol. Experimental solutions were prepared in metal-free glass containers and filled into HDPE vials that were capped with either a classic line spray pump system or a metal-free APF spray pump system, as described in Example 2. The sealed, ready-to-use spray devices containing the experimental dexpanthenol-free budesonide solutions were stored for six months, as described in Example 2, with the following variations: a) Storage at 25°C / 60% relative humidity (rh) b) Storage at 30°C / 75% relative humidity (rh) c) Store at 40°C / 75% relative humidity (rh)

[0060] Not surprisingly, the best stability results, i.e., the least drug loss, were determined for samples using the APF spray pump system and the spray device sealed in an oxygen-impermeable bag. From the results shown in Table 2 and Figures 9A, 9B, 10A, and 10B, it can also be deduced that storage temperature has a clear, but relatively low, effect on the long-term stability of budesonide preparations provided and stored in metal-free containers in accordance with the present invention. Furthermore, the dexpanthenol-free preparations are associated with reduced drug loss and reduced impurity levels, particularly impurity D, compared to the dexpanthenol-supplemented sample preparations of Examples 1 and 2. [Table 2]

[0061] conclusion The results disclosed above indicate that the effect of primary and secondary packaging on impurity formation in experimental samples of liquid budesonide formulations is most pronounced with respect to the observed formation of impurity D, which is not surprising given that impurity D is an oxidation product of budesonide.

[0062] In general, the levels of impurity D were higher in primary containers sealed with APTAR Classic Line pumps compared to primary containers sealed with APF nasal spray pumps from the same manufacturer. This observation may be due to the fact that the Classic Line pumps contain two metal parts in the fluid path, namely, a steel spring and a check valve ball, which may come into contact with the liquid budesonide formulation, causing leakage of some metal ions, which are known to catalyze and thus accelerate the formation of impurity D. On the other hand, the APF nasal spray pumps do not contain any metal elements that may come into contact with the liquid material.

[0063] Samples stored without sealing in oxygen-impermeable bags generally showed the highest levels of impurity D, followed by vials sealed in these bags without an oxygen absorber. However, no significant positive effect of sealing samples in oxygen-impermeable protective bags without removing oxygen from the atmosphere inside the bags was observed.

[0064] The lowest levels of impurity D in the vials equipped with the Classic Line pump were found in the vials sealed with oxygen and water absorbing sachets in impermeable bags.

[0065] The levels of impurity D observed in vials sealed with the APTAR APF pump were significantly lower than those fitted with the Classic Line pump. For the Classic line pump, the highest levels of impurity D were observed in vials stored unsealed in impermeable bags, followed by vials sealed without oxygen absorbers in these bags. The lowest overall levels of impurity D were found in vials sealed in impermeable bags with oxygen- and water-absorbing sachets.

[0066] Indeed, there was no further increase in impurity D levels in the APF sealed vials beyond the 3-month time point. After 6 months of storage at 25 and 40° C., the relative concentrations of impurity D only increased to 0.18 and 0.42% (relative to budesonide), respectively. With such low impurity D levels, it appears possible to provide a packaging system that allows for storage of the product for up to 12, or 18, or even 24 months at room temperature.

[0067] At the same time, the data also indicate that adverse storage conditions, such as at increased temperatures of 40°C (which may occur, for example, during transport of a ready-to-use preparation to its final destination in a hot and humid region, or during storage in a retail store without refrigeration in a tropical or subtropical region), may not be as detrimental to the budesonide preparation as might be expected, provided that suitable packaging is used in accordance with the present invention.

[0068] The presence of catalytically active metal ions appears to substantially deteriorate the quality of buffered, slightly acidic aqueous budesonide preparations during storage, even when oxygen ingress protection measures are applied. This can be derived from the observation that preparations that came into contact with metal parts of the manufacturing and / or filling equipment generally had higher levels of impurity D, even in sealed, oxygen-depleted packaging. This observation was also confirmed by the fact that, despite the formulations being filled into non-metallic glass or HDPE vials, sealing the vials with a metal-containing Classic Line pump was sufficient to produce increased levels of impurity D, even when the vials were sealed in oxygen-impermeable bags as secondary packaging.

[0069] However, the level of impurity R is unaffected by sealing and oxygen depletion, from which it can be concluded that the reaction between 3AP and budesonide does not proceed via the initial formation of impurity D and reaction of the primary amine in 3AP with the C21-aldehyde group of impurity D.

[0070] From the above disclosure and examples, it can be further derived that the best results, i.e., the lowest overall impurity levels in the present aqueous buffered budesonide formulations, are achieved with a formulation comprising α-escin as the only saponin component and containing no dexpanthenol, wherein said formulation is prepared in a non-metallic container and transferred, typically after sterilization, using metal-free filling equipment to a metal-free container, preferably made of glass or HDPE, which is capped and sealed with a metal-free spray pump for nasal delivery, or the sprayable liquid cannot come into contact with metal parts of the spray pump, e.g., the APTAR APF nasal spray pump, and is further packaged in a sealed, oxygen-depleted, preferably also moisture-depleted, oxygen-impermeable secondary packaging.

Claims

1. 1. A spray device comprising a container and a spray pump system, said container filled with a buffered aqueous composition comprising budesonide solubilized therein, said buffered aqueous composition comprising: a buffer adjusted to a pH of 4-5, preferably adjusted to pH 4.3; propylene glycol at a concentration of 5-15% v / v, preferably 10% v / v; aescin, preferably α-escin, at a concentration of 0.1-1 mg / ml, preferably 0.3 mg / ml, as the sole saponin component; EDTA at a concentration of 0.5-2 mg / ml, preferably 1.0 mg / ml; Optionally, dexpanthenol at a concentration of 5-50 mg / ml; and solubilized budesonide at a nominal starting concentration of at least 100 μg / mL, preferably at least 200 μg / mL, typically 200-400 μg / mL; 1. A spray device comprising: a buffered aqueous composition comprising a mixture of ingredients prepared in a metal-free container and stored in the container of the spray device, the container being made of metal-free material and being capped and sealed with a spray pump system suitable for nasal or buccal delivery of the aqueous buffered composition; and the capped and sealed spray device being a primary packaging container for the aqueous buffered composition, which is hermetically sealed in an oxygen-impermeable and oxygen-free secondary packaging container, the latter preferably containing an oxygen absorber and, optionally, also a moisture absorber.

2. 10. The spray device of claim 1, wherein the portion of the primary packaging container containing the spray pump system that is in physical contact with the buffered aqueous composition during storage and / or operation is made of a metal-free material.

3. 3. A spray device according to claim 1 or 2, characterized in that the container containing the aqueous buffer composition is made of metal-free glass or HDPE.

4. The spray device according to any one of claims 1 to 3, characterized in that the aqueous buffer composition does not contain ions of transition metals selected from the group consisting of zinc, copper, cobalt, manganese, iron, nickel, cadmium, vanadium, molybdenum, titanium, and mercury.

5. 5. A nebulizer device according to any one of claims 1 to 4, characterized in that after storage at 20-25°C for a period of 12 months, the aqueous buffer composition contains at least 90%, preferably at least 95%, of the nominal starting concentration of solubilized budesonide and less than or equal to 1% of total impurities, including impurities R and D, relative to the solubilized budesonide concentration.

6. The spray device according to any one of claims 1 to 5, characterized in that the buffer in the aqueous buffer composition is a citrate buffer, a phosphate buffer, or a combination of both.

7. A spray device according to any one of claims 1 to 6, adapted for local or systemic application, preferably adapted as a nasal or mouth spray.

8. 8. A spray device according to any one of claims 1 to 7, filled with a buffered aqueous composition comprising budesonide solubilised therein for use as a pharmaceutical, preferably for use as a pharmaceutical in the treatment of an inflammatory disease or condition.

9. 9. The spray device for use according to claim 8, wherein the inflammatory disease or condition is selected from inflammation of the respiratory passages, lungs, intestines, mucosal tissue, and skin.

10. 8. Use of a spray device according to any one of claims 1 to 7 for the manufacture of a medicament, preferably a medicament useful in the treatment of an inflammatory disease or condition, said inflammatory disease or condition preferably being selected from inflammation of the respiratory passages, lungs, intestines, mucosal tissue, and skin.

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